Abstract
We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington’s disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD. We found that the HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and can also be readily detected in the sensory motor cortex, hippocampus and cerebellum of post-mortem brains from HD individuals, particularly in those with early onset disease. This finding will have important implications for strategies to lower mutant HTT levels in patients and the design of future therapeutics.
Highlights
Huntington’s disease (HD) is a devastating neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene (HTT)[1]
We found that SRSF6, a general splicing factor, tightly binds to the CAG repeat expansion[4]
We developed specific protocols to quantify human HTTexon[1] transcript levels and showed that this small mRNA is produced in HD patients
Summary
HTTexon[1] mRNA is produced in patient derived fibroblast lines with large CAG repeat expansions. We demonstrate that HTTexon[1] transcripts are present in patient derived fibroblast lines with long CAG repeats (Fig. 1) and in the cerebellum, hippocampus and sensory motor cortex (Fig. 2) of HD patient brains. The HTTexon[1] mRNA is readily detectable in fibroblast cell lines (Fig. 1) and post mortem brain samples (Fig. 2) from patients with juvenile CAG repeat lengths. In samples with repeat lengths in the adult onset range, the levels of the HTTexon[1] mRNA were lower than in the juvenile range, and in some cases comparable to levels in control brains. We know from mouse models, that the exon 1 HTT protein is highly pathogenic and very aggregation prone It may only be present at relatively low levels in the tissues from HD patients with adult onset disease. Strategies that lower the levels of HTTexon[1], as well as the full length HTT transcript, and thereby target the probable source of aggregate nucleation, might be expected to have an even greater therapeutic value
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